The long-term objective of this proposal is the prevention of autoimmune mediated Type 1 diabetes mellitus (T1D). Many promising interventions must be tested in a safe and efficient manner in order to achieve this goal. A well-organized cooperative network of capable institutes, Type 1 Diabetes TrialNet, has greatly facilitated the prompt completion of many clinical trials needed to test these potential interventions. The application responds to the RFA to select the clinical centers that will form TrialNet for the next 3 to 5 years. The first goal of this proposal is to both continue and improve the infrastructure essential to completing the current TrialNet studies seeking to prevent T1D in subjects at risk for T1D and to preserve endogenous insulin secretion in subjects with new onset T1D. This section of the proposal reviews Stanford's seven-year experience as a TrialNet national center in central California. The proposal highlights Stanford's plans for extending and improving recruitment and retention activities for the next 3 to 5 years. These plans include both completing the current TrialNet studies and implementing the expected upcoming trials. Stanford is particularly excited about the soon to start TrialNet protocol, developed by Stanford, to test the glucose sensor enhanced strict glycemic control in subjects with new onset T1D. The second goal proposes a clinical study to develop and test a novel intervention using modified autologous dendritic cell therapy to preserve endogenous insulin secretion in subjects with new onset T1D in a multicenter TrialNet study. The proposal, Transgenic IL-4 expression by autologous dendritic cells in new onset Type 1 diabetes (aDC/IL-4), articulates Stanford's approach to testing this therapy in a collaborative manner with other centers in TrialNet. Studies using dendritic cells therapeutically have demonstrated no significant adverse events, so that it is now reasonable to consider this innovative approach as a possible therapy for diabetes prevention. This proposal describes both Phase 1 safety studies followed by Phase 2 efficacy studies using aDC/IL-4. Ultimately, this therapy will likely have a role in preventing T1D PUBLIC HEALTH RELEVANCE: Type 1 diabetes mellitus is a serious life limiting disease that strikes predominantly in children and adolescents. The TrialNet clinical research network, the focus of the proposal, is charged with designing and conducting studies aimed at preventing or delaying the onset or progression of type 1 diabetes, both highly relevant public health goals